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Jouni Uitto – One of the best experts on this subject based on the ideXlab platform.

  • premature termination codon read through in the ABCC6 gene potential treatment for pseudoxanthoma elasticum
    Journal of Investigative Dermatology, 2013
    Co-Authors: Yong Zhou, Qiujie Jiang, Shunshuge Takahagi, Changxia Shao, Jouni Uitto
    Abstract:

    Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder manifesting with ectopic connective tissue mineralization, caused by mutations in the ABCC6 gene, with ∼35% of all mutations being premature termination mutations. In this study, we investigated the therapeutic potential of the nonsense codon read-through-inducing drug, PTC124, in treating PXE. The ability of this drug to facilitate read-through of nonsense mutations was examined in HEK293 cells transfected with human ABCC6 expression constructs harboring seven different PXE-associated nonsense mutations, and was evaluated by immunofluorescence and In-Cell ELISA. Our data demonstrated that PTC124 did not exhibit cytotoxicity in concentrations up to 20μgml −1 , and the facilitated read-through varied not only with dose but also with sequence context. Considering the redundancy of the genetic code, it was postulated that in case of the most common recurrent nonsense mutation, p.R1141X, the read-through may result in substitution of the arginine 1,141 by glycine, tryptophan, or cysteine. Their potential pathogenicity was tested in a recently developed zebrafish messenger RNA (mRNA) rescue assay, and demonstrated that all three mRNA transcripts were able to rescue ABCC6a morpholino-induced phenotype of zebrafish. Thus, our results suggest that read-through of nonsense mutations in ABCC6 by PTC124 may have potential for pharmacologic treatment of PXE.

  • ABCC6 does not transport vitamin k3 glutathione conjugate from the liver relevance to pathomechanisms of pseudoxanthoma elasticum
    Biochemical and Biophysical Research Communications, 2011
    Co-Authors: Krisztina Fulop, Qiujie Jiang, Koen Van De Wetering, Viola Pomozi, Pal Szabo, Tamas Aranyi, Balazs Sarkadi, Piet Borst, Jouni Uitto, Andras Varadi
    Abstract:

    Vitamin K is a cofactor required for gamma-glutamyl carboxylation of several proteins regulating blood clotting, bone formation and soft tissue mineralization. Vitamin K3 is an important intermediate during conversion of the dietary vitamin K1 to the most abundant vitamin K2 form. It has been suggested that ABCC6 may have a role in transporting Vitamin K or its derivatives from the liver to the periphery. This activity is missing in pseudoxanthoma elasticum, a genetic disorder caused by mutations in ABCC6 characterized by abnormal soft tissue mineralization. Here we examined the efflux of the glutathione conjugate of vitamin K3 (VK3GS) from the liver in wild type and ABCC6−/− mice, and in transport assays in vitro. We found in liver perfusion experiments that VK3GS is secreted into the inferior vena cava, but we observed no significant difference between wild type and ABCC6−/− animals. We overexpressed the human ABCC6 transporter in Sf9 insect and MDCKII cells and assayed its Vitamin K3-conjugate transport activity in vitro. We found no measurable transport of VK3GS by ABCC6, whereas ABCC1 transported this compound at high rate in these assays. These results show that VK3GS is not the essential metabolite transported by ABCC6 from the liver and preventing the symptoms of pseudoxanthoma elasticum.

  • targeted ablation of abcc1 or abcc3 in ABCC6 mice does not modify the ectopic mineralization process
    Experimental Dermatology, 2007
    Co-Authors: Qiujie Jiang, Jennifer Larusso, John F. Klement, Alan C. Sartorelli, Martin G. Belinsky, Gary D. Kruh, Jouni Uitto
    Abstract:

    Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by ectopic mineralization of connective tissues, with considerable intra- and interfamiliar phenotypic variability. PXE is caused by mutations in the ABCC6 gene, which encodes a transporter protein, MRP6, and targeted ablation of ABCC6 in mice recapitulates the manifestations of PXE. In this study, we examined the hypothesis that the expression of other members of the Abcc family may be altered in ABCC6 null mice, possibly explaining the phenotypic variability because of the functional overlap of these transporters. Analysis of the transcript levels of Abcc1-10 and 12 in the liver of ABCC6 (-/-) mice by quantitative RT-PCR indicated that the levels of other C family mRNAs were not significantly different from wild-type mice. Next, we developed ABCC6/1(-/-) and ABCC6/3(-/-) double null mice and examined them for tissue mineralization. Histopathologic examination, coupled with computerized morphometric analysis, and chemical assay of calcium x phosphate product in the muzzle skin of Abcc1(-/-) and Abcc3(-/-) mice did not reveal evidence of mineralization. ABCC6/1(-/-) and ABCC6/3(-/-) double knock-out mice exhibited connective tissue mineralization similar to that in ABCC6 (-/-) mice. These results emphasize the importance of the ABCC6 gene in the ectopic mineralization process and further suggest that other members of the Abcc family, particularly Abcc1 and Abcc3, do not modulate the effects of ABCC6 in this mouse model.

Olivier Le Saux – One of the best experts on this subject based on the ideXlab platform.

  • The ABCC6 Transporter: A New Player in Biomineralization
    International journal of molecular sciences, 2017
    Co-Authors: Guillaume Favre, Krisztina Fulop, Tamas Aranyi, Olivier Le Saux, Audrey Laurain, Flóra Szeri, Christophe Duranton, Gilles Kauffenstein, Ludovic Martin, G. Leftheriotis
    Abstract:

    Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of the pivotal role of ectopic mineralization that is preponderant in the elastin-rich tissues of the skin, eyes and blood vessel walls. After discovery of the causative gene of the disease in 2000, the function of the ABCC6 protein remains elusive. More than 300 mutations have been now reported and the concept of a dermal disease has progressively evolved toward a metabolic disorder resulting from the remote effects caused by lack of a circulating anti-mineralization factor. Very recently, evidence has accumulated that this anti-mineralizing factor is inorganic pyrophosphate (PPi). This leads to decreased PPi/Pi (inorganic phosphate) ratio that results from the lack of extracellular ATP release by hepatocytes and probably renal cells harboring the mutant ABCC6 protein. However, the mechanism by which ABCC6 dysfunction causes diminished ATP release remains an enigma. Studies of other ABC transporters, such as ABCC7 or ABCC1 could help our understanding of what ABCC6 exact function is. Data and a hypothesis on the possible roles of ABCC6 in acquired metabolic diseases are also discussed.

  • Abstract 17417: ABCC6 Deficiency Promotes Atherosclerosis
    Circulation, 2015
    Co-Authors: Christopher Brampton, Ludovic Martin, Li-hsieh Chen, Ailea Apana, Georges Leftheriotis, Sara Mccurdy, William A. Boisvert, Olivier Le Saux
    Abstract:

    Introduction: Vascular calcification is associated with aging and common conditions such as hypercholesterolemia and certain genetic disorders. A molecular pathway inhibiting ectopic calcification is initiated by ABCC6, a membrane transporter primarily expressed in liver. ABCC6 facilitates the cellular efflux of ATP from hepatocytes, which is rapidly converted into pyrophosphate (PPi) in the liver vasculature. ABCC6 is responsible for the majority of the PPi release from the liver, and ~60% of plasma PPi in both in humans and mice. As PPi is a major inhibitor of calcification, mutations in ABCC6 underlie the currently incurable calcification disorder pseudoxanthoma elasticum (PXE), some cases of generalized arterial calcification of infancy (GACI). Hypothesis: Multiple lines of evidence have suggested a pathological synergy between ABCC6 and hyperlipidemia. Methods: We examined crosses between ABCC6-/- and Ldlr-/- mice and serum samples from human PXE patients. Three mouse genotypes were generated Ldlr-/-, Ldlr-/-xABCC6-/- and Ldlr-/- xABCC6+/-. Results: When subjected to a high fat diet, mice with reduced or no ABCC6 expression displayed a 2-fold increase of atherosclerotic plaque area (p=0.0001). Interestingly, atherosclerotic plaque was also found in ABCC6-deficient mice fed a normal diet but not in control Ldlr-/- animals. Aortic calcification was not significantly affected by ABCC6 expression except in Ldlr-/-xABCC6-/- mice fed regular chow (p=0.0001). We observed an increased proliferation of smooth muscle cells of but no increase in monocyte-macrophage infiltration in the plaque of Ldlr-/-xABCC6-/- mice. Importantly, we determined that the cholesterol efflux from isolated macrophages towards HDL (mediated by ABCG1) was significantly decreased (-28%, p=0.006) in Ldlr-/-xABCC6-/- mice while the efflux towards ApoA1 (mediated by ABCA1) was unchanged. The analysis of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions in these mice showed altered profiles similar to those found with human PXE plasma samples. Conclusions: Our results indicated that, in addition to being an important inhibitor of vascular calcification, ABCC6 inhibits atherogenesis by modulating reverse cholesterol transport.

  • HNF4alpha and NF-E2 are key transcriptional regulators of the murine ABCC6 gene expression.
    Biochimica et biophysica acta, 2006
    Co-Authors: Vanessa Douet, Christopher M. Vanwart, Matthew B. Heller, Sabrina Reinhard, Olivier Le Saux
    Abstract:

    Mutations in an ABC transporter gene called ABCC6 are responsible for pseudoxanthoma elasticum (PXE), a rare heritable disease characterized by elastic fiber calcification in skin, ocular and vascular tissues. The presumed function of this ABC transporter is to export metabolites from polarized cells. However, the endogenous substrate(s) are unknown and the exact relationship with elastic fibers is unclear. As ABCC6 is only expressed at high level in liver and kidneys, tissues seemingly unrelated to the PXE phenotype, we explored the transcriptional regulation of the murine ABCC6 gene to define the transcriptional signal conferring tissue specificity and to gather clues on its possible biological function. We cloned 2.9 kb of the mABCC6 5′-flanking region and several deletion constructs linked to a luciferase reporter gene. We delineated a proximal promoter and a liver-specific enhancer region. We also demonstrated that the proximal region is a TATA-less promoter requiring an intact CCAAT-box and Sp1 binding for its basal activity. By using reporter assays and chromatin immunoprecipitations, we showed that HNF4alpha and surprisingly, NF-E2, enhanced the mABCC6 promoter activity. The involvement of both HNF4alpha and NF-E2 in the mABCC6 gene regulation suggests that ABCC6 might be involved in a detoxification processes related to hemoglobin or heme.

Andras Varadi – One of the best experts on this subject based on the ideXlab platform.

  • ABCC6 does not transport vitamin k3 glutathione conjugate from the liver relevance to pathomechanisms of pseudoxanthoma elasticum
    Biochemical and Biophysical Research Communications, 2011
    Co-Authors: Krisztina Fulop, Qiujie Jiang, Koen Van De Wetering, Viola Pomozi, Pal Szabo, Tamas Aranyi, Balazs Sarkadi, Piet Borst, Jouni Uitto, Andras Varadi
    Abstract:

    Vitamin K is a cofactor required for gamma-glutamyl carboxylation of several proteins regulating blood clotting, bone formation and soft tissue mineralization. Vitamin K3 is an important intermediate during conversion of the dietary vitamin K1 to the most abundant vitamin K2 form. It has been suggested that ABCC6 may have a role in transporting Vitamin K or its derivatives from the liver to the periphery. This activity is missing in pseudoxanthoma elasticum, a genetic disorder caused by mutations in ABCC6 characterized by abnormal soft tissue mineralization. Here we examined the efflux of the glutathione conjugate of vitamin K3 (VK3GS) from the liver in wild type and ABCC6−/− mice, and in transport assays in vitro. We found in liver perfusion experiments that VK3GS is secreted into the inferior vena cava, but we observed no significant difference between wild type and ABCC6−/− animals. We overexpressed the human ABCC6 transporter in Sf9 insect and MDCKII cells and assayed its Vitamin K3-conjugate transport activity in vitro. We found no measurable transport of VK3GS by ABCC6, whereas ABCC1 transported this compound at high rate in these assays. These results show that VK3GS is not the essential metabolite transported by ABCC6 from the liver and preventing the symptoms of pseudoxanthoma elasticum.

  • Loss of ATP-dependent Transport Activity in Pseudoxanthoma Elasticum-associated Mutants of Human ABCC6 (MRP6)
    The Journal of biological chemistry, 2002
    Co-Authors: Attila Iliás, Balazs Sarkadi, Zsolt Urban, Thomas L. Seidl, Olivier Le Saux, Emese Sinkó, Charles D. Boyd, Andras Varadi
    Abstract:

    Abstract Mutations in the ABCC6 (MRP6) gene cause pseudoxanthoma elasticum (PXE), a rare heritable disorder resulting in the calcification of elastic fibers. In the present study a cDNA encoding a full-length normal variant of ABCC6 was amplified from a human kidney cDNA library, and the protein was expressed in Sf9 insect cells. In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated. We found that glutathione conjugates, including leukotriene C4 and N-ethylmaleimideS-glutathione (NEM-GS), were actively transported by human ABCC6. Organic anions (probenecid, benzbromarone, indomethacin), known to interfere with glutathione conjugate transport of human ABCC1 and ABCC2, inhibited the ABCC6-mediated NEM-GS transport in a specific manner, indicating that ABCC6 has a unique substrate specificity. We have also expressed three missense mutant forms of ABCC6, which have recently been shown to cause PXE. MgATP binding was normal in these proteins; ATP-dependent NEM-GS or leukotriene C4 transport, however, was abolished. Our data indicate that human ABCC6 is a primary active transporter for organic anions. In the three ABCC6 mutant forms examined, the loss of transport activity suggests that these mutations result in a PXE phenotype through a direct influence on the transport activity of this ABC transporter.